147084-10-4

Alcaftadine, a histamine H₁/H₂ receptor antagonist, was approved in the United States in 2010 for the prevention of itching and redness associated with allergic conjunctivitis. Seasonal and perennial allergic conjunctivitis affects up to 40% of the population worldwide. There are numerous treatment options, with topical antihistamines being an effective therapy. Some of the primary symptoms and signs of allergic conjunctivitis are ocular itching and conjunctival redness. The pharmaceutical market for conjunctivitis is substantial and steadily increasing.

Janssen Research Foundation (United States)

Alcaftadine is a H1 histamine receptor antagonist. Alcaftadine is used to prevent eye irritation and treat the signs and symptoms of allergic conjunctivitis.

ChEBI: An imidazobenzazepine that is 6,11-dihydro-5H-imidazo[2,1-b][3]benzazepine substituted at position 3 by a formyl group and at position 11 by a 1-methylpiperidin-4-ylidene group. An antihistamine used for treatment of allergi conjunctivitis.

LastacaftTM

Alcaftadine, an ophthalmic histamine H1 receptor antagonist, was approved by the FDA for the prevention of itching associated with allergic conjunctivitis and was launched under the trade name Lastacaft in early 2011. Alcaftadine was discovered by Janssen Pharmaceuticals and marketed by Vistakon Pharmaceuticals, both subsidiaries of Johnson & Johnson. However, unlike other marketed drugs, the synthesis of alcaftadine was only mentioned in the patents filed by Janssen’s scientists approximately twenty years ago.

The synthetic route described in the scheme is based on the discovery route disclosed in those patents. 1-(2-Phenylethyl)- 1H-imidazole 7 is now commercially available, otherwise it could be prepared by reacting imidazole (5) with 2-phenylethyl bromide (6). With pyridine and triethylamine as base, imidazole 7 was reacted with acyl chloride 8 to provide piperidinecarboxylate 9 in 34% yield, followed by acid hydrolysis with 48% HBr aqueous solution to obtain piperidine dihydrobromide 10 in 98% yield. The N-methylation of 10 was acheived by Leuckart reaction with formaldehyde and formic acid to give 4-methylpiperidine 11 in 82% yield. Treatment of 11 with trifluoromethanesulfonic acid followed by subsequent basification triggered an intramolecular alkylation¨Cdehydration reaction to generate benzazepine 12. Next, alcohol 13 was obtained by prolonged exposure (7 days) of 12 to hydroxymethylation conditions using 40% aqueous formaldehyde. Oxidation of 13 with manganese (IV) oxide provided alcaftadine (II). The yields of last three steps from compound 11 to alcaftadine (II) were not provided in the patent.

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